Rictor/mammalian target of rapamycin 2 regulates the development of notch1 induced murine T-cell acute lymphoblastic leukemia via forkhead box O3

Chunlan Hua, Huidong Guo, Jiachen Bu, Mi Zhou, Hui Cheng, Fuhong He, Jinhong Wang, Xiaomin Wang, Yinchi Zhang, Qianfei Wang, Jianfeng Zhou, Tao Cheng, Mingjiang Xu, Weiping Yuan

Research output: Contribution to journalArticle

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Abstract

Mammalian target of rapamycin (mTOR) is composed of two distinct biochemical complexes, mTORC1 and mTORC2. In response to nutrients and growth factors, mTORC1 is known to control cellular growth by regulating the translational regulators S6 kinase 1 and 4E binding protein 1, whereas mTORC2 mediates cell proliferation and survival by activating Akt through phosphorylation at Ser473. Studies have shown that the deregulation of mTORC2 leads to the development of myeloproliferative disorder and leukemia in the phosphatase and tensin homolog deleted on chromosome ten (PTEN)-deleted mouse model. However, the mechanism by which mTORC2 specifically affects leukemogenesis is still not fully understood. Here, we investigated the role of mTORC2 in NOTCH1-driven T-cell acute lymphoblastic leukemia (T-ALL) in a Rictor-deficient mouse model. We found that, by deleting Rictor, an essential component of mTORC2, leukemia progression was significantly suppressed by arresting a greater proportion of Rictor▵/▵ leukemic cells at the G0 phase of the cell cycle. Furthermore, the absence of Rictor led to the overexpression of chemotaxis-related genes, such as CCR2, CCR4 and CXCR4, which contributed to the homing and migration of Rictor-deficient T-ALL cells to the spleen but not the bone marrow. In addition, we demonstrated that inactivation of mTORC2 caused the overexpression of forkhead box O3 and its downstream effectors and eased the progression of leukemia in T-ALL mice. Our study thus indicates that forkhead box O3 could be a potential drug target for the treatment of T-ALL leukemia.

Original languageEnglish (US)
Pages (from-to)1031-1040
Number of pages10
JournalExperimental Hematology
Volume42
Issue number12
DOIs
StatePublished - Dec 1 2014
Externally publishedYes

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Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
Sirolimus
Leukemia
Ribosomal Protein S6 Kinases
T-Cell Leukemia
Myeloproliferative Disorders
Cell Cycle Resting Phase
Chemotaxis
TOR complex 2
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Phosphoric Monoester Hydrolases
Cell Survival
Intercellular Signaling Peptides and Proteins
Cell Cycle
Carrier Proteins
Spleen
Chromosomes
Bone Marrow
Phosphorylation
Cell Proliferation

ASJC Scopus subject areas

  • Cancer Research
  • Cell Biology
  • Genetics
  • Molecular Biology
  • Hematology

Cite this

Rictor/mammalian target of rapamycin 2 regulates the development of notch1 induced murine T-cell acute lymphoblastic leukemia via forkhead box O3. / Hua, Chunlan; Guo, Huidong; Bu, Jiachen; Zhou, Mi; Cheng, Hui; He, Fuhong; Wang, Jinhong; Wang, Xiaomin; Zhang, Yinchi; Wang, Qianfei; Zhou, Jianfeng; Cheng, Tao; Xu, Mingjiang; Yuan, Weiping.

In: Experimental Hematology, Vol. 42, No. 12, 01.12.2014, p. 1031-1040.

Research output: Contribution to journalArticle

Hua, C, Guo, H, Bu, J, Zhou, M, Cheng, H, He, F, Wang, J, Wang, X, Zhang, Y, Wang, Q, Zhou, J, Cheng, T, Xu, M & Yuan, W 2014, 'Rictor/mammalian target of rapamycin 2 regulates the development of notch1 induced murine T-cell acute lymphoblastic leukemia via forkhead box O3', Experimental Hematology, vol. 42, no. 12, pp. 1031-1040. https://doi.org/10.1016/j.exphem.2014.08.006
Hua, Chunlan ; Guo, Huidong ; Bu, Jiachen ; Zhou, Mi ; Cheng, Hui ; He, Fuhong ; Wang, Jinhong ; Wang, Xiaomin ; Zhang, Yinchi ; Wang, Qianfei ; Zhou, Jianfeng ; Cheng, Tao ; Xu, Mingjiang ; Yuan, Weiping. / Rictor/mammalian target of rapamycin 2 regulates the development of notch1 induced murine T-cell acute lymphoblastic leukemia via forkhead box O3. In: Experimental Hematology. 2014 ; Vol. 42, No. 12. pp. 1031-1040.
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AU - Guo, Huidong

AU - Bu, Jiachen

AU - Zhou, Mi

AU - Cheng, Hui

AU - He, Fuhong

AU - Wang, Jinhong

AU - Wang, Xiaomin

AU - Zhang, Yinchi

AU - Wang, Qianfei

AU - Zhou, Jianfeng

AU - Cheng, Tao

AU - Xu, Mingjiang

AU - Yuan, Weiping

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